ABSTRACT PROJECT 2: METABOLIC FACTORS AND ALZHEIMER DISEASE Type 2 diabetes mellitus (T2DM) increases Alzheimer's disease (AD) risk by ~1.5 times, but the mechanisms are unclear. We focus on two metabolic risk-related mechanisms that may link early T2DM to AD: insulin & insulin-like growth factor 1 (IGF1) and cholesterol transport. In non-demented adults, we relate these metabolic factors to 1) cerebrospinal fluid (CSF) markers of AD pathology, 2) structural and functional brain connectivity and hippocampal subregion thickness in regions selectively vulnerable to AD, and 3) changes over 2 years in brain connectivity and memory. Our multimodal longitudinal project includes multi-shell diffusion tensor imaging analyzed with a novel fiber orientation distribution tool. These innovations improve our ability to measure brain connectivity even in the presence of crossed fibers and white matter lesions. We also will use resting state functional magnetic resonance imaging (rs-fMRI) to assess functional connectivity, and will evaluate entorhinal cortex and hippocampal CA1 thickness. We will examine 180 adults with no or mild cognitive impairment; aged 70-90 yrs. We will recruit subjects with low vascular risk, with hypertension, and those with elevated glycated hemoglobin and low HDL-C. Using continuous measures of insulin, IGF1, IGF binding proteins, and cholesterol efflux capacity derived from blood and CSF, we will evaluate: 1) How IGF1 and IGFBPs relate to neurodegeneration, mediated by CSF ptau181 levels and measured as atrophy in the entorhinal cortex and CA1 of the hippocampus and loss of functional and structural connectivity in AD-relevant regions; 2) How insulin and cholesterol efflux capacity relate to demyelination and functional connectivity deficits in AD-relevant regions, mediated by A?42 levels; and 3) How insulin signaling peptides and cholesterol efflux capacity are related to 2-year changes in cognition, and brain structure and function. We anticipate improved understanding of how T2DM and metabolic risk contribute to preclinical AD brain changes. This is crucial to enabling tailored treatment and prevention efforts to persons at specific risk.